Systemic lupus erythematosus and rheumatoid arthritis

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
To my wife and my daughters 
 
 
 
 
 
 

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ABSTRACT 
 
Systemic lupus erythematosus and rheumatoid arthritis 
- Analyses of candidate genes, involved in immune functions, for susceptibility and severity. 
 
Martin Johansson, Department of Public Health and Clinical Medicine, Rheumatology, 
Umeå University 
 
Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease with systemic 
manifestations characterized by auto-antibodies directed against different parts of the cell nucleus 
including DNA, histones and ribosomes. The systemic inflammation can cause damage to 
multiple organs, 
e.g.
, kidneys, skin, heart, lungs and the nervous system. Rheumatoid arthritis 
(RA) is another autoimmune rheumatic disease characterized by auto-antibodies, mainly directed 
against the Fc-part of immunoglobulin G (rheumatoid factor (RF)) but also against citrullinated 
peptides/proteins (ACPAs). The inflammation in RA primarily involves the joints resulting in 
inflamed synovial tissue and destruction of cartilage. The aetiology of both SLE and RA is 
unclear but there is a genetic contribution predominantly of genes involved in inflammation. The 
diseases are believed to be multifactorial, or complex, meaning that multiple genes interact with 
environmental, infectious and hormonal factors, thus increasing the risk of developing disease. 
The aim of this study was to investigate different candidate genes involved in functions of the 
immune system and their relationship with SLE and RA susceptibility and severity.
The patients and controls were from the four northernmost counties of Sweden, which is a 
fairly homogenous population well suited for genetic studies. Two single nucleotide 
polymorphisms (SNPs) in the oestrogen receptor 
α
(
ESR1
) gene were analysed in SLE. No 
association was found between the SNPs and SLE 
per se
however the minor alleles (
PvuII
C and 
XbaI
G) were associated with skin manifestations and later disease onset, thus representing a 
milder form of the disease. A SNP in the programmed cell-death 1 (
PDCD1
) gene, which codes 
for PD-1, an inhibitory molecule involved in T-cell activation, was studied. No association was 
seen between the risk allele (
PD-1.3
A) and SLE susceptibility but a strong association was found 
with renal disease. A risk allele of the protein tyrosine phosphatase non-receptor type 22 
(
PTPN22
) gene that codes for a protein called Lyp which acts as a negative regulator of T-cell 
receptor (TCR) signalling was significantly associated with SLE
 
in three different case-control 
sets across Sweden. Both 
PDCD1
and 
PTPN22
were independently associated with renal disease. 
The 
PTPN22
gene has been associated with numerous autoimmune diseases and was evaluated in 
another auto-antibody producing disease, RA. From the Medical Biobank of northern Sweden 
samples donated before the development of symptoms of RA were identified. In these individuals, 
who subsequently developed RA, the 1858T risk allele in combination with ACPAs gave a high 
relative risk (>132) for developing RA. The association between 
PTPN22
and RA was confirmed 
in a larger material of patients with early RA. The 1858T allele, of the three SNPs investigated, 
was shown to be the true risk allele associated with auto-antibody positive RA. A functional role 
of 
PTPN22
in TCR-mediated activation of T cells from patients with SLE and RA was not 
demonstrated.
In conclusion, minor alleles of two SNPs in the 
ESR1 
gene were associated with a milder form 
of SLE. The risk allele in the 
PDCD1
gene was associated with renal disorder in SLE. The risk 
allele 1858T of the 
PTPN22
gene was associated with SLE, particularly with renal disease. The 
1858T allele in combination with auto-antibodies was a risk factor for developing RA. In early 
diagnosed RA, the 1858T allele was highly associated with RA and in particular with auto-
antibody positive RA.